Skip to main content

Advertisement

SpringerLink
Log in

Effect of axitinib on the QT interval in healthy volunteers

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1–3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization.

Methods

The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration–QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily).

Results

Axitinib and ketoconazole had opposite effects on heart rate: Axitinib lowered it, ketoconazole raised it. The final analysis showed a flat relationship between QTc and axitinib concentration (slope −0.0314 ms·mL/ng) for axitinib alone. Mean highest placebo-matched change from baseline in QTc was −3.0 [90 % confidence interval (CI) −5.4, −0.6] ms. At supratherapeutic axitinib exposures achieved with potent cytochrome P450 3A4/5 inhibition by ketoconazole, the model predicted mean QTc change of 6.5 (90 % CI 4.4–8.5) ms. The slope population mean estimate was −0.331 (95 % CI −0.860, 0.198) ms·mL/µg for ketoconazole alone and 0.0725 (0.0445–0.1005) ms·mL/ng for axitinib in the presence of ketoconazole. The results were then compared with those obtained based on more widely used Fridericia’s, Bazett’s, and study-specific correction methods.

Conclusions

Since axitinib plasma concentrations observed in this study exceeded the range of concentrations observed in patients with RCC at the highest approved clinical dose (10 mg twice daily), axitinib was not associated with clinically significant QTc prolongation in target populations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Roden DM (2008) Cellular basis of drug-induced torsades de pointes. Br J Pharmacol 154:1502–1507. doi:10.1038/bjp.2008.238

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. U.S. Department of Health and Human Services Food and Drug Administration (2005) Guidance for industry, E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129357.pdf. Accessed 4 Feb 2013

  3. Hu-Lowe DD, Zou HY, Grazzini ML, Hallin ME, Wickman GR, Amundson K, Chen JH, Rewolinski DA, Yamazaki S, Wu EY, McTigue MA, Murray BW, Kania RS, O’Connor P, Shalinsky DR, Bender SL (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 14:7272–7283. doi:10.1158/1078-0432.CCR-08-0652

    Article  CAS  PubMed  Google Scholar 

  4. Inlyta® (axitinib) prescribing information (2012). http://labeling.pfizer.com/ShowLabeling.aspx?id=759. Accessed 22 Jan 2013

  5. Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, Reich SD, Freddo JL, Wilding G (2005) Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol 23:5474–5483. doi:10.1200/JCO.2005.04.192

    Article  CAS  PubMed  Google Scholar 

  6. Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou Y-C, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ (2011) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378:1931–1939. doi:10.1016/S0140-6736(11)61613-9

    Article  CAS  PubMed  Google Scholar 

  7. Di Lorenzo G, Porta C, Bellmunt J, Sternberg C, Kirkali Z, Staehler M, Joniau S, Montorsi F, Buonerba C (2011) Toxicities of targeted therapy and their management in kidney cancer. Eur Urol 59:526–540. doi:10.1016/j.eururo.2011.01.002

    Article  PubMed  Google Scholar 

  8. Chen Y, Tortorici MA, Garrett M, Hee B, Klamerus KJ, Pithavala YK (2013) Clinical pharmacology of axitinib. Clin Pharmacokinet 52:713–725. doi:10.1007/s40262-013-0068-3

    Article  CAS  PubMed  Google Scholar 

  9. Pithavala YK, Tong W, Mount J, Rahavendran SV, Garrett M, Hee B, Selaru P, Sarapa N, Klamerus KJ (2012) Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers. Invest New Drugs 30:273–281. doi:10.1007/s10637-010-9511-6

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Tornoe CW, Garnett CE, Wang Y, Florian J, Li M, Gobburu JV (2011) Creation of a knowledge management system for QT analyses. J Clin Pharmacol 51:1035–1042. doi:10.1177/0091270010378408

    Article  PubMed  Google Scholar 

  11. Garnett CE, Zhu H, Malik M, Fossa AA, Zhang J, Badilini F, Li J, Darpo B, Sager P, Rodriguez I (2012) Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects. Am Heart J 163:912–930. doi:10.1016/j.ahj.2012.02.023

    Article  PubMed  Google Scholar 

  12. Sweeney KR, Gastonguay MR, Benincosa L, Cronenberger CL, Glue P, Malhotra BK (2010) Exposure–response modeling and clinical trial simulation of the effect of tolterodine on QT intervals in healthy volunteers. Drug Discov Ther 4:44–53

    CAS  PubMed  Google Scholar 

  13. Desai M, Li L, Desta Z, Malik M, Flockhart D (2003) Variability of heart rate correction methods for the QT interval. Br J Clin Pharmacol 55:511–517. doi:10.1046/j.1365-2125.2003.01791.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Bello CL, Mulay M, Huang X, Patyna S, Dinolfo M, Levine S, Van Vugt A, Toh M, Baum C, Rosen L (2009) Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic–pharmacodynamic evaluation of sunitinib. Clin Cancer Res 15:7045–7052. doi:10.1158/1078-0432.CCR-09-1521

    Article  CAS  PubMed  Google Scholar 

  15. Chien JY, Lucksiri A, Ernest CS 2nd, Gorski JC, Wrighton SA, Hall SD (2006) Stochastic prediction of CYP3A-mediated inhibition of midazolam clearance by ketoconazole. Drug Metab Dispos 34:1208–1219. doi:10.1124/dmd.105.008730

    Article  CAS  PubMed  Google Scholar 

  16. Tortorici MA, Toh M, Rahavendran SV, Labadie RR, Alvey CW, Marbury T, Fuentes E, Green M, Ni G, Hee B, Pithavala YK (2011) Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics. Invest New Drugs 29:1370–1380. doi:10.1007/s10637-010-9477-4

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Garnett CE, Beasley N, Bhattaram VA, Jadhav PR, Madabushi R, Stockbridge N, Tornoe CW, Wang Y, Zhu H, Gobburu JV (2008) Concentration–QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol 48:13–18. doi:10.1177/0091270007307881

    Article  CAS  PubMed  Google Scholar 

  18. Russell T, Riley SP, Cook JA, Lalonde RL (2008) A perspective on the use of concentration–QT modeling in drug development. J Clin Pharmacol 48:9–12. doi:10.1177/0091270007311115

    Article  CAS  PubMed  Google Scholar 

  19. Chapel S, Hutmacher MM, Bockbrader H, de Greef R, Lalonde RL (2011) Comparison of QTc data analysis methods recommended by the ICH E14 guidance and exposure–response analysis: case study of a thorough QT study of asenapine. Clin Pharmacol Ther 89:75–80. doi:10.1038/clpt.2010.220

    Article  CAS  PubMed  Google Scholar 

  20. Darpo B, Garnett C, Benson CT, Keirns J, Leishman D, Malik M, Mehrotra N, Prasad K, Riley S, Rodriguez I, Sager P, Sarapa N, Wallis R (2014) Cardiac Safety Research Consortium: Can the thorough QT/QTc study be replaced by early QT assessment in routine clinical pharmacology studies? Scientific update and a research proposal for a path forward. Am Heart J 168:262–272. doi:10.1016/j.ahj.2014.06.003

    Article  PubMed  Google Scholar 

  21. Darpo B, Sarapa N, Garnett C, Benson C, Dota C, Ferber G, Jarugula V, Johannesen L, Keirns J, Krudys K, Ortemann-Renon C, Riley S, Rogers-Subramaniam D, Stockbridge N (2014) The IQ-CSRC prospective clinical phase 1 study: “Can early QT assessment using exposure response analysis replace the thorough QT study?”. Ann Noninvasive Electrocardiol 19:70–81. doi:10.1111/anec.12128

    Article  PubMed  Google Scholar 

  22. Darpo B, Nebout T, Sager PT (2006) Clinical evaluation of QT/QTc prolongation and proarrhythmic potential for nonantiarrhythmic drugs: the international conference on harmonization of technical requirements for registration of pharmaceuticals for human use E14 guideline. J Clin Pharmacol 46:498–507. doi:10.1177/0091270006286436

    Article  CAS  PubMed  Google Scholar 

  23. Zhu H, Wang Y, Gobburu JV, Garnett CE (2010) Considerations for clinical trial design and data analyses of thorough QT studies using drug–drug interaction. J Clin Pharmacol 50:1106–1111. doi:10.1177/0091270009358710

    Article  PubMed  Google Scholar 

  24. Rock EP, Finkle J, Fingert HJ, Booth BP, Garnett CE, Grant S, Justice RL, Kovacs RJ, Kowey PR, Rodriguez I, Sanhai WR, Strnadova C, Targum SL, Tsong Y, Uhl K, Stockbridge N (2009) Assessing proarrhythmic potential of drugs when optimal studies are infeasible. Am Heart J 157:827–836. doi:10.1016/j.ahj.2009.02.020

    Article  CAS  PubMed  Google Scholar 

  25. Curigliano G, Spitaleri G, Fingert HJ, de Braud F, Sessa C, Loh E, Cipolla C, De Pas T, Goldhirsch A, Shah R (2008) Drug-induced QTc interval prolongation: a proposal towards an efficient and safe anticancer drug development. Eur J Cancer 44:494–500. doi:10.1016/j.ejca.2007.10.001

    Article  CAS  PubMed  Google Scholar 

  26. Malhotra BK, Glue P, Sweeney K, Anziano R, Mancuso J, Wicker P (2007) Thorough QT study with recommended and supratherapeutic doses of tolterodine. Clin Pharmacol Ther 81:377–385. doi:10.1038/sj.clpt.6100089

    Article  CAS  PubMed  Google Scholar 

  27. Li J, Birmingham B, Mosqueda-Garcia R, Sander N, Newbold P, Sager P (2008) Evaluation of drug-induced QT/QTc prolongation in the presence of drug inducted changes in heart rate using population PK/PD modeling approach: sibenadet experience. In: American conference on pharmacometrics (ACoP) annual meeting, Tucson, AZ., Mar 9–12, 2008

  28. Kosoglou T, Salfi M, Lim JM, Batra VK, Cayen MN, Affrime MB (2000) Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine. Br J Clin Pharmacol 50:581–589. doi:10.1046/j.1365-2125.2000.00290.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Chaikin P, Gillen MS, Malik M, Pentikis H, Rhodes GR, Roberts DJ (2005) Co-administration of ketoconazole with H1-antagonists ebastine and loratadine in healthy subjects: pharmacokinetic and pharmacodynamic effects. Br J Clin Pharmacol 59:346–354. doi:10.1111/j.1365-2125.2005.02348.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Robert M, Salva M, Segarra R, Pavesi M, Esbri R, Roberts D, Golor G (2007) The prokinetic cinitapride has no clinically relevant pharmacokinetic interaction and effect on QT during coadministration with ketoconazole. Drug Metab Dispos 35:1149–1156. doi:10.1124/dmd.106.010835

    Article  CAS  PubMed  Google Scholar 

  31. Sarapa N, Britto MR (2008) Challenges of characterizing proarrhythmic risk due to QTc prolongation induced by nonadjuvant anticancer agents. Expert Opin Drug Saf 7:305–318. doi:10.1517/14740338.7.3.305

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was sponsored by Pfizer Inc. Medical writing support was funded by Pfizer Inc and provided by Mariko Nagashima, PhD, of Engage Scientific Solutions (Southport, CT, USA).

Conflict of interest

Ana Ruiz-Garcia, Brett E. Houk, and Yazdi K. Pithavala are employees of and own stock in Pfizer Inc. Michael A. Tortorici, who was employed by and owned stock in Pfizer Inc during the time of this study and development of the manuscript, is currently an employee of CSL Behring Biotherapies for Life™. Melvin Toh, who was employed by and owned stock/options in Pfizer Inc at the time of this study, is currently an employee of CK Life Sciences Int’l. (Holdings) Inc and no longer owns stock/options in Pfizer Inc. Nenad Sarapa, who was employed by and owned stock/options in Pfizer Inc at the time of this study, is currently employed by Bayer Healthcare Pharmaceuticals.

Author information

Authors and Affiliations

  1. Clinical Pharmacology, Pfizer Inc, San Diego, CA, USA

    Ana Ruiz-Garcia, Brett E. Houk, Yazdi K. Pithavala & Michael A. Tortorici

  2. CK Life Sciences Int’l (Holdings) Inc, Hong Kong, China

    Melvin Toh

  3. Clinical Pharmacology-Oncology, Bayer Healthcare Pharmaceuticals, Montville, NJ, USA

    Nenad Sarapa

  4. Clinical Pharmacology and Pharmacometrics, CSL Behring Biotherapies for Life™, 1020 First Avenue, King of Prussia, PA, 19406, USA

    Michael A. Tortorici

Authors
  1. Ana Ruiz-Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brett E. Houk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yazdi K. Pithavala
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Melvin Toh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nenad Sarapa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael A. Tortorici
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael A. Tortorici.

Additional information

M. A. Tortorici was employed at Pfizer Inc during the time of this study and development of the manuscript.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ruiz-Garcia, A., Houk, B.E., Pithavala, Y.K. et al. Effect of axitinib on the QT interval in healthy volunteers. Cancer Chemother Pharmacol 75, 619–628 (2015). https://doi.org/10.1007/s00280-015-2677-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-015-2677-z

Keywords

Search

Navigation